Download Flunitrazepam

Flunitrazepam
Done by:
Neda’a Al-Muallem
Introduction
• Flunitrazepam (formerly marketed under
the trade name Rohypnol )
• is a powerful hypnotic drug which is a
benzodiazepine derivative. It has powerful
hypnotic, sedative, anxiolytic, and skeletal
muscle relaxant properties. The drug is
sometimes abused as a date rape drug.
History
• Flunitrazepam was first synthesized in the early
1970s by Roche and was used in hospitals when
deep sedation was needed. It first entered the
commercial market in Europe in 1975, and in
the 1980s it began to be available in other
countries. It first appeared in the U.S. in the early
1990s.
• It originally came in 1 mg, 2 mg, and 5 mg
doses, but due to its potency and potential for
abuse the higher doses were soon taken off the
market and it is now only available in 1 mg.
Pharmacology
• flunitrazepam's pharmacological effects
include sedation, muscle relaxation,
reduction in anxiety, and prevention of
convulsions .
• However, flunitrazepam's effects are
approximately 7 to 10 times more potent
than diazepam.
Cont.
• The effects of flunitrazepam appear
approximately 15 to 20 minutes after oral
administration, and last for approximately
four to six hours. Some residual effects
can persist up to 12 hours or more after
administration.
Medical uses
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In the United States, the drug has not been approved by the Food and
Drug Administration for medical use, and is considered to be an illegal
drug.
In the United Kingdom, the drug is available only by private prescription.
Though Rohypnol was discontinued in 1986, Rohypnol use is still present
in modern culture; among other uses, it is used in some hospitals to sedate
patients undergoing colonoscopy.
In Australia, prescription is restricted. It is used primarily for the treatment
of severe insomnia that has not responded to other treatments.
In South Africa, Rohypnol is classified as a schedule 6 drug in. It is
available by prescription only, and restricted to 1 mg doses. Travelers from
South Africa to the United States are limited to a 30-day supply. The drug
must be declared to US Customs upon arrival. If a valid prescription
cannot be produced, the drug may be subject to Customs search and
seizure, and the traveler may face criminal charges or deportation.
In Norway, Rohypnol has been withdrawn from market because of its
reputation, but the drug is still available under the brand-name Flunipam.
Drug-facilitated sexual assault
• Flunitrazepam is known to induce
anterograde amnesia in sufficient doses;
individuals are unable to remember
certain events that they experienced while
under the influence of the drug. This
effect is particularly dangerous when
flunitrazepam is used to aid in the
commission of sexual assault; victims may
not be able to clearly recall the assault, the
assailant, or the events surrounding the
assault.
• If flunitrazepam exposure is to be detected at all, urine
samples need to be collected within 72 hours and
subjected to sensitive analytical tests.
• The problem is compounded by the onset of amnesia
after ingestion of the drug, which causes the victim to
be uncertain about the facts surrounding the rape. This
uncertainty may lead to critical delays or even reluctance
to report the rape and provide appropriate biological
samples for testing.
• If a person suspects that he or she is the victim of a
flunitrazepam-facilitated rape, he or she should get
laboratory testing for flunitrazepam as soon as possible.
• It must be noted that an inability to remember events,
including sexual encounters, is not conclusive evidence
of having consumed a drugged drink: Drunkenness
itself causes blackouts, sleepiness, and a reduction in
inhibitions. Only a timely screening for flunitrazepam
can demonstrate its use.
• It has been shown that alcohol alone is the substance
used in the vast majority of cases of date-rape. A recent
study conducted by doctors in the U.K. found that none
of the subjects reporting spiked drinks had any traces of
flunitrazepam or other medications popularly believed
to be associated with rape such as GHB. The study
claims that binge drinking was to blame.
Drug-facilitated robbery
• In the United Kingdom, the use of flunitrazepam and
other "date rape" drugs has been connected to stealing
from sedated victims. One expert quoted in a British
tabloid estimated that up to 2,000 individuals are robbed
each year after being spiked with powerful sedatives,
making drug-assisted robbery a more common problem
than drug-assisted rape.
• Criminals sometimes use flunitrazepam before
committing robbery as it has a calming and anti-emotive
effect. This allows the criminal to perform the robbery
without becoming anxious. Flunitrazepam is also known
to induce anterograde amnesia making police
interrogations more difficult.
Recreational drug
• flunitrazepam has become widely known in USA for its use as a
date-rape drug, it is used more frequently as a recreational drug. It is
used by high school and college students, rave party attendees, and
heroin and cocaine users (who call a dose of flunitrazepam a
"roofie") for recreational purposes, including:
• To produce profound intoxication (Kurt Cobain overdosed on a
mixture of flunitrazepam and champagne several weeks before his
death)
• To boost the high produced by heroin, or ease the anxiety and/or
sleeplessness of withdrawal
• To counteract the side effects of stimulants (e.g. insomnia,
paranoia, jitteriness)
• To "soften" the so-called "crash" which follows heavy usage of
stimulants, such as cocaine or methamphetamine
• To improve sex drive and appetite.
Cont.
• Flunitrazepam is usually consumed orally,
and is often combined with alcohol. It is
also occasionally insufflated (i.e. tablets
are crushed into powder and snorted). In
some European countries, there was an
alcohol solution of flunitrazepam
(Darkene), taken by injection, with very
strong effects.
Side effects
• Flunitrazepam is considered to be one of the most addictive of the
benzodiazepines, along with clonazepam, midazolam, alprazolam,
and particularily, temazepam, nitrazepam, and nimetazepam. Its use
causes several notable side effects, including:
• Drowsiness
• Loss of motor control
– Dizziness
– Lack of coordination
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Slurred speech
Amnesia
Confusion
Gastrointestinal disturbances, lasting 12 or more hours.
Respiratory depression in higher doses
Cont.
• Long-term use of flunitrazepam can
result in psychological and physical
dependence and the appearance of
withdrawal symptoms when the drug is
discontinued.
• Flunitrazepam impairs cognitive and
psychomotor functions, affecting reaction
time and driving skill. The use of this
drug in combination with alcohol
potentiates these side effects, and can lead
to toxicity.
HPLC analysis
• A new analytical methodology was developed for
simultaneous high-performance liquid chromatographic
quantitation of nitrazepam, estazolam, flunitrazepam,
and triazolam in plasma. After addition of the internal
standard nor-prazepam, biological samples and
calibration standards were extracted at basic pH into
diethyl ether-methylene chloride (2:1, v/v). The
reconstituted extract was separated on a reversed-phase
Nova Pak C18 column with acidic buffer (6mM)acetonitrile-methanol (64:23:13, v/v) as mobile phase.
The detection was performed at 242 nm. Within-run
and day-to-day precision values were about 2-8%.
• The method is thus sensitive and reproducible for use
in clinical and experimental toxicokinetic studies.
Gas chromatographic analysis
• A rapid method for the determination of flunitrazepam and
desmethylflunitrazepam in human serum in the range 10-300 ng/ml
is described. Both drugs are isolated from biological material by
means of a single extraction, part of the organic phase is
evaporated to dryness and the residue is dissolved in a small volume
of benzene. Without further purification, the substance is
determined gas chromatographically with an electron-capture
detector configuration of 63Ni-type. The method permits the
quantitative determination of at least 25-300 ng/ml with an overall
recovery of flunitrazepam of 99.7 +/- 4.9% and of
desmethylflunitrazepam of 98.6 +/- 7.8% from serum. All
calculations were carried out by a data system that was programmed
for this purpose. The limit of detection for flunitrazepam is of the
order of 1 ng/ml in serum.
• The method is sufficiently sensitive and specific for therapy control
purposes. The time needed for an analysis is less than 1 h.
Hair Analysis using GC–MS-NCI
• The method involved decontamination of hair samples
with dichloromethane, incubation in Sorenson buffer
(pH 7.6) in the presence of diazepam-d5 used as internal
standard, direct liquid–liquid extraction with
diethylether–chloroform (80:20, v/v), derivatization with
heptafluorobutyric anhydride and analysis by gas
chromatography coupled to mass spectrometry in the
negative chemical ionization mode of detection.
Flunitrazepam and its major metabolite, 7-aminoflunitrazepam, were both detected. The concentrations
determined in the proximal hair segment were 89.5 and
24.0 pg/mg for flunitrazepam and 7-aminoflunitrazepam, respectively.
PRECAUTIONS
1. Benzodiazepines should not be used alone to treat
depression or anxiety associated with depression. Suicide
may be precipitated in such patients.
2. The should not be used for phobic or obsessional states.
3. They should not be used for the treatment of chronic
psychosis.
4. In cases of loss or bereavement, psychological
adjustment may be inhibited by benzodiazepines.
5. Disinhibiting effects may be manifested in various ways.
Suicide may be precipitated in patients who are
depressed, and aggressive behaviour towards self and
others may be precipitated.
Extreme caution should therefore be used in prescribing
benzodiazepines in patients with personality disorders.
Cont.
6. The lowest dose which can control the
symptoms should be used. It should not be
continued beyond four weeks.
7. Long-term chronic use is not recommended.
8. Treatment should always be tapered off
gradually.
9. Patients who have taken benzodiazepines for a
long time may require a longer period during
which doses are reduced.
10. When a benzodiazepine is used as a hypnotic,
treatment should, if possible, be intermittent.